Small Molecules can Provide New Knowledge About Type 2 Diabetes

Ingela Lanekoff is a Professor at Uppsala University’s Department of Chemistry – BMC. She has also received the internationally sought-after ERC Starting Grant this year. The grant funds a project that aims to develop new methods for studying small molecules in individual cells, and the methods will increase our knowledge of type 2 diabetes.

“In this type of diabetes, the beta cells have worked well before, but for various reasons they become stressed and reduce their secretion of insulin. It has been established that this is caused by changes in the intracellular metabolism. But what really happens inside the cell is still largely unknown. We will establish new analytical techniques to map the cell's metabolism and identify where it falters. Since not all beta cells behave in the same way, we will look at small molecules – a molecular class called metabolites – in individual cells with time-resolved measurements. No existing technology for analysing metabolites can follow a cell's behaviour in this manner,” says Ingela Lanekoff.

Until now, researchers have been limited to looking at cells in large groups, frozen or incubated, but now Ingela Lanekoff and her colleagues want to be able to look at a single cell and see what happens to its smaller molecules in real time. This will be undertaken with the aid of mass spectrometry where molecules are detected according to mass and charge.

“Mass spectrometry is like a very sensitive scale that allows us to detect which metabolites are present. We can see thousands of different molecules in each scan, without having to select or label them before analysis. To detect metabolites from as small an amount as a single cell is a big analytical challenge that we expect will take up half the project. Once we have established the methodology, we will then combine the measurements of metabolites with measurements of the cell's RNA. Through RNA, we can understand the conditions that the cell has, and how, in turn, this relates to how it behaves with its metabolites,” says Ingela Lanekoff.

The Decisive Step

After developing new techniques for studying small molecules – time-resolved and in individual cells – the methodology will be applied to human beta cells to increase our knowledge about type 2 diabetes.

“Drugs or lifestyle changes can make the cells start working again, but if we can find out in which step the beta cells become fatigued, we can then take the right measures more quickly. We hope to identify early risk factors so that the patient may avoid becoming ill with type 2 diabetes to begin with. Eventually, I hope that it will be possible to find the missing link and reverse the behaviour of the malfunctioning beta cells. With the project, we will lay the foundation, a platform to build on,” says Ingela Lanekoff.

In developing the technique, the research team will use model cells that can be cultivated. In the application phase however, they will look at donated cells from humans. The ERC grant will finance new instrumentation and expand the research group. The latter will grow from five to eight doctoral students and get two postdoctoral fellows. The project also involves collaborations across area boundaries:

“Thanks to the Uppsala Diabetes Centre, I have met Professor Sebastian Barg who will now be assistant supervisor for one of the doctoral students. He has knowledge in insulin secretion that I lack. It is always easy to end up in your own subject bubble, but research centres such as this one are great because we can find new angles and collaborations. When researchers who are at the forefront talk to each other, it creates synergies and opportunities to do new things together. Through the diabetes centre, we become aware of valuable competences nearby that we might otherwise not have even known about.”

Anton Nyström

Photograph: Mikael Wallerstedt